BACKGROUND:The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial (Further ...Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease (PAD) as well as the effect on major adverse limb events.
METHODS:FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years. Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of <0.85, or if they had a prior peripheral vascular procedure. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization. The key secondary end point was a composite of cardiovascular death, myocardial infarction, or stroke. An additional outcome of interest was major adverse limb events defined as acute limb ischemia, major amputation, or urgent peripheral revascularization for ischemia.
RESULTS:Three thousand six hundred forty-two patients (13.2%) had PAD (1505 with no prior myocardial infarction or stroke). Evolocumab significantly reduced the primary end point consistently in patients with PAD (hazard ratio HR 0.79; 95% confidence interval CI, 0.66–0.94; P=0.0098) and without PAD (HR 0.86; 95% CI, 0.80–0.93; P=0.0003; Pinteraction=0.40). For the key secondary end point, the HRs were 0.73 (0.59–0.91; P=0.0040) for those with PAD and 0.81 (0.73–0.90; P<0.0001) for those without PAD (Pinteraction=0.41). Because of their higher risk, patients with PAD had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the key secondary end point (3.5% with PAD, 1.4% without PAD). Evolocumab reduced the risk of major adverse limb events in all patients (HR, 0.58; 95% CI, 0.38–0.88; P=0.0093) with consistent effects in those with and without known PAD. There was a consistent relationship between lower achieved low-density lipoprotein cholesterol and lower risk of limb events (P=0.026 for the beta coefficient) that extended down to <10 mg/dL.
CONCLUSIONS:Patients with PAD are at high risk of cardiovascular events, and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions. Moreover, lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT01764633.
Peripheral artery disease (PAD) stems from atherosclerosis of lower extremity arteries with resultant arterial narrowing or occlusion. The most severe form of PAD is termed chronic limb-threatening ...ischemia and carries a significant risk of limb loss and cardiovascular mortality. Diabetes mellitus is known to increase the incidence of PAD, accelerate disease progression, and increase disease severity. Patients with concomitant diabetes mellitus and PAD are at high risk for major complications, such as amputation. Despite a decrease in the overall number of amputations performed annually in the United States, amputation rates among those with both diabetes mellitus and PAD have remained stable or even increased in high-risk subgroups. Within this cohort, there is significant regional, racial/ethnic, and socioeconomic variation in amputation risk. Specifically, residents of rural areas, African-American and Native American patients, and those of low socioeconomic status carry the highest risk of amputation. The burden of amputation is severe, with 5-year mortality rates exceeding those of many malignancies. Furthermore, caring for patients with PAD and diabetes mellitus imposes a significant cost to the healthcare system—estimated to range from $84 billion to $380 billion annually. Efforts to improve the quality of care for those with PAD and diabetes mellitus must focus on the subgroups at high risk for amputation and the disparities they face in the receipt of both preventive and interventional cardiovascular care. Better understanding of these social, economic, and structural barriers will prove to be crucial for cardiovascular physicians striving to better care for patients facing this challenging combination of chronic diseases.
The age-adjusted prevalence of peripheral arterial disease in the US population was estimated to approach 12% in 1985, and as the population ages, the overall population having peripheral arterial ...disease is predicted to rise. The clinical consequences of occlusive peripheral arterial disease include intermittent claudication, that is, pain with walking, and critical limb ischemia (CLI), which includes pain at rest and loss of tissue integrity in the distal limbs, which may ultimately lead to amputation of a portion of the lower extremity. The risk factors for CLI are similar to those linked to coronary artery disease and include advanced age, smoking, diabetes mellitus, hyperlipidemia, and hypertension. The worldwide incidence of CLI was estimated to be 500 to 1000 cases per million people per year in 1991. The prognosis is poor for CLI subjects with advanced limb disease. One study of >400 such subjects in the United Kingdom found that 25% required amputation and 20% (including some subjects who had required amputation) died within 1 year. In the United States, ≈280 lower-limb amputations for ischemic disease are performed per million people each year. The first objective in treating CLI is to increase blood circulation to the affected limb. Theoretically, increased blood flow could be achieved by increasing the number of vessels that supply the ischemic tissue with blood. The use of pharmacological agents to induce new blood vessel growth for the treatment or prevention of pathological clinical conditions has been called therapeutic angiogenesis. Since the identification of the endothelial progenitor cell in 1997 by Asahara and Isner, the field of cell-based therapies for peripheral arterial disease has been in a state of continuous evolution. Here, we review the current state of that field.
Chronic limb-threatening ischemia (CLTI) is associated with mortality, amputation, and impaired quality of life. These Global Vascular Guidelines (GVG) are focused on definition, evaluation, and ...management of CLTI with the goals of improving evidence-based care and highlighting critical research needs. The term CLTI is preferred over critical limb ischemia, as the latter implies threshold values of impaired perfusion rather than a continuum. CLTI is a clinical syndrome defined by the presence of peripheral artery disease (PAD) in combination with rest pain, gangrene, or a lower limb ulceration >2 weeks duration. Venous, traumatic, embolic, and nonatherosclerotic etiologies are excluded. All patients with suspected CLTI should be referred urgently to a vascular specialist. Accurately staging the severity of limb threat is fundamental, and the Society for Vascular Surgery Threatened Limb Classification system, based on grading of Wounds, Ischemia, and foot Infection (WIfI) is endorsed. Objective hemodynamic testing, including toe pressures as the preferred measure, is required to assess CLTI. Evidence-based revascularization (EBR) hinges on three independent axes: Patient risk, Limb severity, and ANatomic complexity (PLAN). Average-risk and high-risk patients are defined by estimated procedural and 2-year all-cause mortality. The GVG proposes a new Global Anatomic Staging System (GLASS), which involves defining a preferred target artery path (TAP) and then estimating limb-based patency (LBP), resulting in three stages of complexity for intervention. The optimal revascularization strategy is also influenced by the availability of autogenous vein for open bypass surgery. Recommendations for EBR are based on best available data, pending level 1 evidence from ongoing trials. Vein bypass may be preferred for average-risk patients with advanced limb threat and high complexity disease, while those with less complex anatomy, intermediate severity limb threat, or high patient risk may be favored for endovascular intervention. All patients with CLTI should be afforded best medical therapy including the use of antithrombotic, lipid-lowering, antihypertensive, and glycemic control agents, as well as counseling on smoking cessation, diet, exercise, and preventive foot care. Following EBR, long-term limb surveillance is advised. The effectiveness of nonrevascularization therapies (eg, spinal stimulation, pneumatic compression, prostanoids, and hyperbaric oxygen) has not been established. Regenerative medicine approaches (eg, cell, gene therapies) for CLTI should be restricted to rigorously conducted randomizsed clinical trials. The GVG promotes standardization of study designs and end points for clinical trials in CLTI. The importance of multidisciplinary teams and centers of excellence for amputation prevention is stressed as a key health system initiative.
Lower extremity peripheral artery disease (PAD) affects >230 million adults worldwide and is associated with increased risk of various adverse clinical outcomes (other cardiovascular diseases such as ...coronary heart disease and stroke and leg outcomes such as amputation). Despite its prevalence and clinical importance, PAD has been historically underappreciated by health care professionals and patients. This underappreciation seems multifactorial (eg, limited availability of the first-line diagnostic test, the ankle-brachial index, in clinics; incorrect perceptions that a leg vascular disease is not fatal and that the diagnosis of PAD would not necessarily change clinical practice). In the past several years, a body of evidence has indicated that these perceptions are incorrect. Several studies have consistently demonstrated that many patients with PAD are not receiving evidence-based therapies. Thus, this scientific statement provides an update for health care professionals regarding contemporary epidemiology (eg, prevalence, temporal trends, risk factors, and complications) of PAD, the present status of diagnosis (physiological tests and imaging modalities), and the major gaps in the management of PAD (eg, medications, exercise therapy, and revascularization). The statement also lists key gaps in research, clinical practice, and implementation related to PAD. Orchestrated efforts among different parties (eg, health care providers, researchers, expert organizations, and health care organizations) will be needed to increase the awareness and understanding of PAD and improve the diagnostic approaches, management, and prognosis of PAD.
Global populations are undergoing a major epidemiological transition in which the burden of atherosclerotic cardiovascular diseases is shifting rapidly from high-income to low-income and ...middle-income countries (LMICs). Peripheral artery disease (PAD) is no exception, so that greater focus is now required on the prevention and management of this disease in less-advantaged countries. In this Review, we examine the epidemiology of PAD and, where feasible, take a global perspective. However, the dearth of publications in LMICs means an unavoidable over-reliance on studies in high-income countries. Research to date suggests that PAD might affect a greater proportion of women than men in LMICs. Although factors such as poverty, industrialization, and infection might conceivably influence the development of PAD in such settings, the ageing of the population and increase in traditional cardiovascular risk factors, such as smoking, diabetes mellitus, and hypertension, are likely to be the main driving forces.
Peripheral Artery Disease: Past, Present, and Future Campia, Umberto; Gerhard-Herman, Marie; Piazza, Gregory ...
The American journal of medicine,
October 2019, 2019-10-00, 20191001, Letnik:
132, Številka:
10
Journal Article
Recenzirano
Peripheral artery disease is a prevalent but underdiagnosed manifestation of atherosclerosis. There is insufficient awareness of its clinical manifestations, including intermittent claudication and ...critical limb ischemia and of its risk of adverse cardiovascular and limb outcomes. In addition, our inadequate knowledge of its pathophysiology has also limited the development of effective treatments, particularly in the presence of critical limb ischemia. This review aims to highlight essential elements of the epidemiology and pathophysiology of peripheral artery disease, bring attention to the often-atypical manifestations of occlusive arterial disease of the lower extremity, increase awareness of critical limb ischemia, briefly describe the diagnostic role of the ankle brachial index, and go over the contemporary management of peripheral artery disease. An emphasis is placed on evidence-based medical treatments to improve symptoms and quality of life and to reduce the risk of cardiovascular and limb events in these patients, including supervised exercise training, smoking cessation, antagonism of the renin-angiotensin system, lipid-lowering, antiplatelet, and antithrombotic therapies.
Lipoprotein-related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, largely on the basis of studies of coronary artery disease (CAD). The relative ...contributions of specific lipoproteins to the risk of peripheral artery disease (PAD) have not been well defined. We leveraged large-scale genetic association data to investigate the effects of circulating lipoprotein-related traits on PAD risk.
Genome-wide association study summary statistics for circulating lipoprotein-related traits were used in the mendelian randomization bayesian model averaging framework to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. Mendelian randomization was used to estimate the effect of apolipoprotein B (ApoB) lowering on PAD risk using gene regions proxying lipid-lowering drug targets. Genes relevant to prioritized lipoprotein subfractions were identified with transcriptome-wide association studies.
ApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability, 0.86;
=0.003) and CAD (marginal inclusion probability, 0.92;
=0.005). Genetic proxies for ApoB-lowering medications were associated with reduced risk of both PAD (odds ratio,0.87 per 1-SD decrease in ApoB 95% CI, 0.84-0.91;
=9×10
) and CAD (odds ratio,0.66 95% CI, 0.63-0.69;
=4×10
), with a stronger predicted effect of ApoB lowering on CAD (ratio of effects, 3.09 95% CI, 2.29-4.60;
<1×10
). Extra-small very-low-density lipoprotein particle concentration was identified as the most likely subfraction associated with PAD risk (marginal inclusion probability, 0.91;
=2.3×10
), whereas large low-density lipoprotein particle concentration was the most likely subfraction associated with CAD risk (marginal inclusion probability, 0.95;
=0.011). Genes associated with extra-small very-low-density lipoprotein particle and large low-density lipoprotein particle concentration included canonical ApoB pathway components, although gene-specific effects were variable. Lipoprotein(a) was associated with increased risk of PAD independently of ApoB (odds ratio, 1.04 95% CI, 1.03-1.04;
=1.0×10
).
ApoB was prioritized as the major lipoprotein fraction causally responsible for both PAD and CAD risk. However, ApoB-lowering drug targets and ApoB-containing lipoprotein subfractions had diverse associations with atherosclerotic cardiovascular disease, and distinct subfraction-associated genes suggest possible differences in the role of lipoproteins in the pathogenesis of PAD and CAD.
To study international differences in incidence and practice patterns as well as time trends in lower limb amputations related to peripheral arterial disease and/or diabetes mellitus.
Data on lower ...limb amputations during 2010–2014 were collected from population based administrative data from countries in Europe and Australasia participating in the VASCUNET collaboration. Amputation rates, time trends, in hospital or 30 day mortality and reimbursement systems were analysed.
Data from 12 countries covering 259 million inhabitants in 2014 were included. Individuals aged ≥ 65 years ranged from 12.9% (Slovakia) to 20.7% (Germany) and diabetes prevalence among amputees from 25.7% (Finland) to 74.3% (Slovakia). The mean incidence of major amputation varied between 7.2/100,000 (New Zealand) and 41.4/100,000 (Hungary), with an overall declining time trend with the exception of Slovakia, while minor amputations increased over time. The older age group (≥65 years) was up to 4.9 times more likely to be amputated compared with those younger than 65 years. Reported mortality rates were lowest in Finland (6.3%) and highest in Hungary (20.3%). Countries with a fee for service reimbursement system had a lower incidence of major amputation compared with countries with a population based reimbursement system (14.3/100,000 versus 18.4/100,000, respectively, p < .001).
This international audit showed large geographical differences in major amputation rates, by a factor of almost six, and an overall declining time trend during the 4 year observation of this study. Diabetes prevalence, age distribution, and mortality rates were also found to vary between countries. Despite limitations attributable to registry data, these findings are important, and warrant further research on how to improve limb salvage in different demographic settings.
Objective/Background The objective was to determine the prevalence and clinical determinants of renal artery stenosis (RAS) in patients undergoing digital subtraction angiography (DSA) for the ...assessment of peripheral artery disease (PAD), and to evaluate its prognostic significance. Methods All DSAs performed from January 2000 to January 2006 were retrospectively reviewed for assessment of PAD in patients naive for any prior revascularisation of lower-limb arteries. All DSA studies were read by two senior physicians blinded to outcome, and consensus was reached in cases of disagreement. RAS was defined as the presence of ≥50% stenosis in either renal artery. Patients' electronic medical files were systematically reviewed and follow-up was completed by contact with family physicians until January 2014. The primary outcome was composite, including death, peripheral revascularisation, or any limb amputation. Secondary outcomes were all-cause mortality, and another composite, including death and non-fatal myocardial infarction or stroke or coronary or carotid revascularisation. Results In total, 400 consecutive patients having a first DSA of lower extremities, two thirds of whom were for critical limb ischaemia, were studied. Thirteen patients were excluded owing to poor renal artery imaging. RAS was detected in 57 patients (14%). Only two factors were independently and significantly associated with RAS in multivariate analysis: diffuse PAD (involving both proximal and distal segments odds ratio {OR} 3.50, 95% confidence interval {CI} 1.16–10.54; p = .026) and decreased glomerular filtration rate (OR 0.55 per 30 mL/minute/1.73 m2 , 95% CI 0.41–0.75; p < .001). During follow-up (mean ± SD 62 ± 47 months), 25% experienced limb amputation and 54% died. In multivariate analysis, no significant association was found between RAS and primary outcome (hazard ratio 0.80; 95% CI 0.57–1.10). No significant association was found with secondary outcomes. Conclusion Incidental RAS is frequent (14%) among patients with PAD undergoing lower extremity imaging. No difference in outcome in patients with RAS versus those without RAS was seen. Larger studies are necessary to draw definite conclusions.
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